Hyperinsulinemia fails to augment ET-1 action in the skeletal muscle vascular bed in vivo in humans.
Endogenous endothelin action is augmented in human obesity and type 2 diabetes and contributes to endothelial dysfunction and impairs insulin-mediated vasodilation in humans. We hypothesized that insulin resistance-associated hyperinsulinemia could preferentially drive endothelin-mediated vasoconstriction. We applied hyperinsulinemic-euglycemic clamps with higher insulin dosing in obese subjects than lean subjects (30 vs. 10 mU.m(-2).min(-1), respectively), with the goal of matching insulin's nitric oxide (NO)-mediated vascular effects. We predicted that, under these circumstances, insulin-stimulated endothelin-1 (ET-1) action (assessed with the type A endothelin receptor antagonist BQ-123) would be augmented in proportion to hyperinsulinemia. NO bioactivity was assessed using the nitric oxide synthase inhibitor N(G)-monomethyl-l-arginine. Insulin-mediated vasodilation and insulin-stimulated NO bioavailability were well matched across groups by this approach. As expected, steady-state insulin levels were approximately threefold higher in obese than lean subjects (109.2 +/- 10.2 pmol/l vs. 518.4 +/- 84.0, P = 0.03). Despite this, the augmentation of insulin-mediated vasodilation by BQ-123 was not different between groups. ET-1 flux across the leg was not augmented by insulin alone but was increased with the addition of BQ-123 to insulin (P = 0.01 BQ-123 effect, P = not significant comparing groups). Endothelin antagonism augmented insulin-stimulated NO bioavailability and NOx flux, but not differently between groups and not proportional to hyperinsulinemia. These findings do not support the hypothesis that insulin resistance-associated hyperinsulinemia preferentially drives endothelin-mediated vasoconstriction.
Lteif
Amale A
AA
Indiana Univ. School of Medicine, Indianapolis, IN 46202, USA.
Fulford
Angie D
AD
Considine
Robert V
RV
Gelfand
Inessa
I
Baron
Alain D
AD
Mather
Kieren J
KJ
D000328:Adult; D000959:Antihypertensive Agents / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D006946:Hyperinsulinism / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology*; D007328:Insulin / Q000494:pharmacology; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000503:physiopathology; D010456:Peptides, Cyclic / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007328:Insulin; D010456:Peptides, Cyclic; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C072247:cyclo(Trp-Asp-Pro-Val-Leu)